Aging, obesity, and type 2 diabetes are major risk factors for colorectal cancer (CRC), which will cause close to 10% of cancer-related deaths in 2010. Identifying the molecular mediators that promote CRC and increase risk with aging, obesity, and diabetes is critical to improved detection, prevention, and treatment. Considerable evidence links elevated levels of plasma insulin to the increased CRC risk with aging, obesity, and diabetes, but the receptor mediating these effects of hyperinsulinemia is unknown. Insulin can bind to and activate both the insulin receptor (IR) and the related insulin-like growth factor-1 receptor (IGF1R). IGF1R is associated with growth and tumorigenesis in the intestinal epithelium, but the role of IR in the intestinal epithelium is not well defined. We have developed a mouse model with intestinal epithelial cell-specific deletion of IR to define the effects of IR loss during adaption to high-fat diet (HFD), over the normal course of aging, and during spontaneous and HFD-associated tumorigenesis. In addition, we have crossed the IR mutant mice to mice expressing EGFP under the promoter for the intestinal epithelial stem cell (IESC) biomarker Sox9. These mice will allow us to directly assess the role of IR in IESC. Our preliminary studies indicate that intestinal epithelial IR deletion decreases expression of differentiation marker sucrase-isomaltase, promotes growth of intestinal crypts in culture, and accelerates formation of aberrant crypt foci (ACF), the earliest precancerous lesions, in the azoxymethane (AOM) model of spontaneous tumorigenesis. This study uses two specific aims to test the central hypothesis that IR normally functions to promote differentiated function of intestinal epithelial cells and limit spontaneous or obesity-associated tumorigenesis. Aim 1 tests the hypothesis that deletion of IR expands IESC and impairs differentiation or differentiated function over the course of high-fat diet-induced obesity and normal aging. Aim 2 tests the hypothesis that intestinal epithelial IR deletion promotes spontaneous or obesity-associated colon tumors. The results of these studies will increase our fundamental understanding of IR in intestinal adaptation to aging and diet-induced obesity, as well as the role of IR in spontaneous and HFD-induced tumorigenesis. This knowledge is critical to improved CRC prevention, detection, and treatment in the face of an expanding aging population, the obesity pandemic, and the rising cost of healthcare. PUBLIC HEALTH RELEVANCE: Elevated levels of circulating insulin contribute to the age-related diseases of obesity, type 2 diabetes, and colorectal cancer. The studies proposed in this application will delineate the molecular mechanisms linking these age-associated pathologies. Understanding the molecular mediators that promote colorectal cancer risk with elevated insulin signaling is paramount to improved diagnosis, treatment, and prevention.